Project Summary/Abstract The majority of blindness and vision impairment in the US are age-related diseases, such as glaucoma and diabetic retinopathy, requiring drug intervention for disease management. The eye has many physical and biological barriers that limit a drug?s bioavailabilty for absorption and restrict systemic drug administration since drug levels required for treatment efficacy may be too toxic to the rest of the body. The complex anatomy and physiology of the eye require highly sophisticated physiologically-based pharmacokinetic (PBPK) model of the eye combined with biophysics-based ocular drug delivery model and whole body pharmacokinetic (PK) and pharmacodynamics (PD) to estimate the PK profile of a drug in the eye after administration. The overall goal of the proposed project is therefore to develop such a unique multiscale- multiphysics model to simulate ocular delivery, absorption, distribution, pharmacokinetics and in vitro to in vivo extrapolation (IVIVE) for generic drugs and drug products. Computational modeling of in vivo ocular drug delivery requires anatomy and physiology of the eye, physicochemical material properties of ocular tissues and barriers as well as physicochemical drug/carrier properties. In Aim 1, high-fidelity models in the form of parametric 2D/3D eye mesh model (human, animal) will be developed, enabling various modes of delivery to be simulated. Aim 2 focuses on the development of a multicompartmental model for ocular drug delivery using a reduced-order model to complement the 3D model from Aim 1. The parameters for the multicompartmental model will be calibrated using the 3D model results and experimental data. It will also be linked to the existing whole body PBPK model. In Aim 3, a database of the fundamental properties of drug products accounting for formulation, morphology, conjugation and interaction with non-biologics will be developed. With the main components developed and integrated, model calibration and validation will be carried out in Aim 4 against available experimental preclinical and clinical data. In Aim 5, mathematical models of typical in vitro transwell-based ocular barriers will be developed, validated, and used in both 3D and compartmental in vivo models to provide a framework for IVIVE. Parametric simulations of drug delivery and PK for brand and generic drugs will be conducted in Aim 6. The novel software tool proposed will be able to provide an accurate and efficient computational platform to virtually test, design, and develop ocular drug products and to facilitate translational applications from bench to bedside, eliminating the high cost and time of in vitro and in vivo experiments.